The present invention belongs to the fields of pharmacology and medicinal chemistry, and provides new pharmaceuticals which are useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to increasing the level of serotonin in the brain and inhibiting the serotonin 1Dxcex1 receptor.
Pharmaceutical researchers have discovered in recent years that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which very strongly affect many psychological and personality-affecting processes as well. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be a key to a very large number of processes which affect both physiological and psychological functions. Drugs which influence the function of serotonin in the brain are accordingly of great importance and are now used for a surprisingly large number of different therapies.
The early generation of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin reuptake, and also to have anticholinergic, antihistamine or anti-alpha-adrenergic activity. More recently, it has become possible to study the function of drugs at individual receptors in vitro or ex vivo, and it has also been realized that therapeutic agents free of extraneous mechanisms of action are advantageous to the patient. Accordingly, the objective of research now is to discover agents which affect only functions of serotonin, for example, at specific identifiable receptors.
Perhaps the most dramatic discovery in medicinal chemistry in the recent past is fluoxetine, a serotonin reuptake inhibitor, which is extremely effective in the treatment of depression. As a reuptake inhibitor, it increases the availability of serotonin in the synapse by reducing the uptake of serotonin by the serotonin uptake carrier. Dysfunction of the serotonin neurons resulting from excessive uptake results in depression, as well as other pathologies of the central nervous system. Not only is fluoxetine spectacularly effective in depression, it is also effective in treating numerous other conditions.
Over the last several years it has become apparent that serotonin is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermo-regulation, sleep, sexual behavior, anxiety, depression, and hallucinogenic behavior [Glennon, R. A., J. Med. Chem., 30, 1 (1987)].
5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2 and 5-HT3 receptors, with the former being further divided into the sub-classes 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E and 5-HT1F.
Few ligands have selectivity for 5-HT1D receptors. Sumatriptan possesses limited 5-HT1D selectivity. GR 127935 has also been identified as a potent and selective 5-HT1D receptor antagonist. Hayer, et al., Pharmacological Reviews, Vol. 46, No. 2, pp. 157-203 (1994).
Molecular cloning has demonstrated that pharmacologically defined 5-HT1D receptors are encoded by two separate but closely related genes, designated 5-HT1Dxcex1and 5-HT1Dxcex2, which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase). Leonhardt, S., et al., J. Neurochem, 53:465-471 (1989).
It is desirable to develop new compounds and treatments for 5-HT1Dxcex1 receptor mediated diseases and diseases mediated by inhibiting the reuptake of serotonin.
We have now discovered a class of compounds which have activity at the 5-HT1Dxcex1 receptor and which inhibit the reuptake of serotonin.
This invention provides a compound of formula I 
wherein
R1 and R2 are each independently hydrogen, halo, xe2x80x94(C1-C6)alkyl or xe2x80x94(C1-C6)alkoxy;
R3 is hydrogen or xe2x80x94(C1-C6)alkyl;
Y is xe2x80x94COxe2x80x94 or xe2x80x94CH2-;
Z is xe2x80x94NHxe2x80x94, xe2x80x94N(COR)xe2x80x94 or xe2x80x94CH2xe2x80x94, where R is xe2x80x94(C1-C6)alkyl or xe2x80x94(C3-C8)cycloalkyl;
 represents a double or single bond; and
n and m are each independently an integer from 1 to 3, both inclusive; or a pharmaceutically acceptable salt or solvate thereof.
This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention further provides a method of inhibiting the reuptake of serotonin comprising administering to a mammal in need thereof, a therapeutically effective amount of a serotonin reuptake inhibitor of formula I.
This invention provides in addition a method of inhibiting the 5-HT1Dxcex1 receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a direct acting 5-HT1Dxcex1 antagonist of formula I.
This invention further provides a method of inhibiting the reuptake of serotonin and inhibiting the 5-HT1Dxcex1 receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a serotonin reuptake inhibitor and 5-HT1D antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the reuptake of serotonin which comprises administering to a mammal in need thereof a therapeutically effective amount of a serotonin reuptake inhibitor of formula I.
Still further, this invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the 5-HT1Dxcex1 receptor which comprises administering to a mammal in need thereof a therapeutically effective amount of a direct acting 5-HT1Dxcex1 antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the reuptake of serotonin and inhibiting the 5-HT1Dxcex1 receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a serotonin reuptake inhibitor and 5-HT1Dxcex1 antagonist of formula I.
Another aspect of the invention is a method of treating a mammal suffering from or susceptible to depression or anxiety; which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I.
Yet another aspect of the invention is a method of treating a condition chosen from the group consisting of obsessive-compulsive disease, obesity, migraine, pain, particularly neuropathic pain, bulimia, premenstrual syndrome or late luteal syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention-deficit hyperactivity disorder, disruptive behavior disorders, impulsive control disorders, borderline personality disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism and trichotilomania, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I.
A still further aspect of the invention is a method of treating a mammal suffering from or susceptible to dementia, Parkinson""s disease, anxiety, appetite modulation, sexual dysfunction, seasonal affective disorder, hyperprolactinemia, cerebral vascular disease, antisocial behavior, obsessive/compulsive disorder, amnesia, tardive dyskensia, hypertension and gastric motility disorder, which comprises administering to a subject in need of such treatment, a therapeutically effective amount of a compound of formula I.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
Definitions:
As used herein, the term, xe2x80x9c(C1-C6)alkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl and the like.
The term xe2x80x9c(C1-C10)alkylxe2x80x9d encompasses xe2x80x9c(C1-C4)alkylxe2x80x9d.
The term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
The term xe2x80x9c(C1-C6)alkoxylxe2x80x9d, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isoproxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexoxy and like groups attached to the remainder of the molecule by the oxygen atom.
The term xe2x80x9c(C3-C8)cycloalkylxe2x80x9d includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl rings.
The term xe2x80x9cprotecting groupxe2x80x9d is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent a functional group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapters 5 and 7 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, and by J. W. Barton in chapter 2 of Protective Groups in Organic Chemistry, J. F. W. McOmie, e., Plenum Press, New York, 1973, which are incorporated herein by reference in their entirety.
Nitrogen protecting groups refer to a group which will prevent an amino group from participating in a reaction. Examples of amino protecting groups include benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula xe2x80x94COOR1 where R1 includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, and p-toluenesulfonyl-aminocarbonyl. A preferred amino-protecting is phthalimidyl.
Useful compounds for practicing the method of the present invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formula I. Acids commonly employed to form such salts are inorganic acids, such as hydrocholoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid, hydrobromic acid and organic acids such as acetic acid, oxalic acid, maleic acid or fumaric acid
Preferred substituent groups of compounds of formula (I) include:
(a) R1 is hydrogen or xe2x80x94(C1-C6)alkyl;
(b) R1 is halo;
(c) R1 is xe2x80x94(C1-C6)alkoxy;
(d) R2 is hydrogen or xe2x80x94(C1-C6)alkyl;
(e) R2 is halo;
(f) R2 is Cl or F;
(g) R2 is xe2x80x94(C1-C6)alkyl or xe2x80x94(C1-C6)alkoxy;
(h) R3 is hydrogen;
(i) R3 is xe2x80x94(C1-C6)alkyl;
(j) n is 1;
(k) m is 1;
(1) Z is xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94;
(m) Z is xe2x80x94N(COR)xe2x80x94;
(n) R is xe2x80x94(C1-C6)alkyl; and
(o) R is xe2x80x94(C3-C8)cycloalkyl.
Compounds where R1 is substituted at the 6-position and R2 is substituted at the 2-position are preferred.
Of these particularly preferred compounds, compounds N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)eth-1-yl)-3-(4-(6-fluoroindol-3-yl)-piperidin-1-yl)propanamide, N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)eth-1-yl)-3-(4-(6-fluoroindol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl)propanamide, N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)eth-1-yl)-3-(4-(6-chloroindol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl)propanamide, 1-(2-methoxyphenyl)-4-(6-(4-(6-chloroindole-3-yl)-1,2,3,6-tetrahydropyridin-1-yl)hex-1-yl)piperazine, N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)eth-1-yl)-3-(4-(6-chloroindol-3-yl)-piperidin1-yl)propanamide, 1-(2-methoxyphenyl)-4-(6-(4-(6-fluoroindole-3-yl)-1piperidin-1-yl)hex-1-yl)piperazine trihydrochloride and 1-(2-methoxyphenyl)-4-(6-(4-(6-chloroindole-3-yl)-piperidin-1-yl)hex-1-yl)piperazine trihydrochloride are especially preferred.
Of these compounds, N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)eth-1-yl)-3-(4-(6-fluoroindol-3-yl)-piperidin-1-yl)propanamide is most preferred.
Compounds of the instant invention where Y is xe2x80x94COxe2x80x94 and Z is xe2x80x94NHxe2x80x94 can be prepared as described in Scheme I, on the following page. 
An appropriately substituted piperazine (1) is N-alkylated with a protected haloalkylamine (2) by refluxing in a suitable solvent, such as acetonitrile, in the presence of an excess of a mild base, such as potassium carbonate, for about 1 to 10 hours to prepare (3). Phthalimidyl is a preferred protecting group.
Deprotection of (3) by, for example, treatment with hydrazine hydrate in ethanol, affords (4). N-acylation of the primary amine (4) can then be accomplished by treating a chilled solution of (4) with acyldihalide (5) in the presence of a base such as pyridine. Initial temperatures of about 0xc2x0 C. are preferred for the reaction which is then allowed to warm to room temperature as it proceeds. Preferably, a halogenated hydrocarbon, such as methylene chloride, is employed as a solvent. The reaction is substantially complete in from 1 to 24 hours.
In a second alkylation step, (7) is coupled with (6) by refluxing together for from 1 to 24 hours in an appropriate solvent with a slight excess of a base such as triethylamine to prepare (8). Preferably, a co-solvent system, such as toluene/isopropanol is employed.
If desired, reduction of the tetrahydropyridine ring of (8) can be readily accomplished by treatment with a mild reducing agent such as triethyl silane in trifluoroacetic acid, preferably in an alkyl halide solvent such as methylene chloride.
Compounds where Y is xe2x80x94CH2xe2x80x94 and Z is xe2x80x94NHxe2x80x94 or xe2x80x94N(COR)xe2x80x94 can be prepared as described in Scheme II, below. 
Compounds where Y is xe2x80x94CH2xe2x80x94, (10), are achieved by refluxing (8) or (9) with a suitable reducing agent, preferably lithium aluminum hydride, in an aprotic polar solvent such as tetrahydrofuran for from about 1 to 24 hours as shown in step (a), above.
Preparation of compounds where Z is xe2x80x94N(COR)xe2x80x94 can be accomplished by acylation of (10) with an appropriate acylhalide (11) of the formula RCOX, where X is halo, preferably chlorine, as shown in step (b), above. Generally, a solution of (10) in an aprotic polar solvent such as tetrahydrofuran is treated with acylhalide (11), preferably dissolved and chilled to about 0xc2x0 C. in tetrahydrofuran. The reaction is allowed to warm to room temperature and proceed until the reaction is complete in about 1 to 24 hours.
As described in Scheme 1, step (e), above, treatment with a reducing agent affords reduction of the tetrahydropyridine double bond.
When Y is xe2x80x94COxe2x80x94, preparation of the desired compound may be accomplished by treating (8) or (9) with a base, such as sodium hydride then reacting with an acyl halide of the formula RCOX as described in part (b).
Compounds of formula I where Y and Z are each independently xe2x80x94CH2xe2x80x94 can be prepared as described in Scheme III, below. 
Substituted piperazine (1) is acylated by treatment with acyldihalide (13). The reaction is preferably initiated at temperatures of about 0xc2x0 C. in a suitable solvent, such as methylene chloride, in the presence of a slight excess of a base, such as pyridine, and allowed to warm to room temperature until substantially complete, in about 1 to 24 hours.
Alkylation of (14) is achieved as described in Scheme I, by refluxing (14) with (15) preferably in a co-solvent system of toluene/isopropanol, in the presence of an excess of a base such as triethylamine.
Reduction of the carbonyl of (16) can then be accomplished by refluxing with a reducing agent such as lithium aluminum hydride in an aprotic polar solvent such as tetrahydrofuran to prepare (17).
Further reduction of the tetrahydropyridine double bond can be accomplished as described in Scheme I, step (e), above.
The intermediates and final products may be isolated and purified by conventional techniques, for example, isolation using silica gel chromatography followed by recrystallization.
It will be readily appreciated by the skilled artisan that the starting materials which are not described are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available.
The following preparations and examples further illustrate the preparation of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.